Brian O'Driscoll has been ruled out of Ireland's RBS 6 Nations clash against Scotland.
The Ireland captain failed to recover from a mild hamstring strain suffered late in Ireland's opening victory over Italy last Sunday.
Ireland coach Eddie O'Sullivan will name a replacement for O'Driscoll after training on Friday.
Meanwhile, O'Driscoll's centre partner Gordan D'Arcy, who also suffered a hamstring strain in Rome, faces a fitness test on Friday morning.
Both Kevin Maggs and Gavin Duffy are on stand-by.
Both O'Driscoll and D'Arcy had been tentatively named in Ireland's starting XV for the clash at Murrayfield as O'Sullivan gave them every chance to recover.
Ireland's rehabilitation specialist Brian Green has been working with the Leinster pair ''24/7'' and they have been making a swift recovery.
But O'Sullivan insisted he would not risk either of his key midfielders and it was decided after a fitness test that O'Driscoll will not shake off his injury in time.
''Both players are recovering extremely quickly but they have just six days and it was decided that O'Driscoll will not be 100% ready by the match,'' said a spokesman with the Irish team.
O'Driscoll was hit from behind in a ruck during injury time of the 28-17 victory against Italy and was trapped on the floor in the splits position.
D'Arcy was withdrawn in the 33rd minute after pulling up at full speed and was replaced at inside centre by Shane Horgan, who is now likely to start in the number 12 shirt at Murrayfield.
Should D'Arcy fail to come through his fitness test, Maggs is the likely replacement at outside centre, with Girvan Dempsey promoted from the bench to start either at wing or full-back.
O'Sullivan has not shied away from the fact that losing one or both of O'Driscoll and D'Arcy - a possible Lions midfield pairing against the All Blacks this summer - would seriously hamper Ireland's championship chances.
Earlier this week, O'Sullivan admitted: "What will affect our chances in the tournament is the health of our squad. I don't think we can cope with too many injuries in certain areas.
"If we keep a healthy side as the tournament unfolds, we will compete. But if we get some injuries in the wrong places - like we have done with Brian and Gordon - then it could have an impact."
He added: "There is no doubting as to how important their fitness is to us."
As head coach Stuart Lancaster polishes the axe he will soon wield over his World Cup training squad, Exeter Chiefs coach Rob Baxter has backed Jack Nowell, Henry Slade and Luke Cowan-Dickie to be given a stay of execution.
Italy Under-20s held off a late Samoa blitz to retain their place in the World Rugby U20 Championship on Saturday and head coach Alessandro Troncon believes the experience will have served as a valuable lesson for his young troops.